Preparation of delta-keto-esters

ABSTRACT

Delta-keto-esters such as 4-oxopentane-1-carboxylic acid methyl ester and the like, are prepared in the presence of a primary amine, a Schiff base, or both, by reacting a ketone having at least one hydrogen atom in the alpha position and an alpha-beta unsaturated carboxylic acid ester in the presence of an acid according to the disclosed invention.

This is a continuation of application Ser. No. 413,436 filed Nov. 7,1973.

The present invention relates to a process for preparingdelta-keto-esters by liquid-phase reaction of an alpha-beta unsaturatedcarboxylic acid ester and a ketone, in which at least one hydrogen atomoccurs in an alpha place in the ketone.

BACKGROUND OF THE INVENTION

It has been proposed in Comptes Rendus 248, 1959, pages 1533-1535 forthe addition reaction of a ketone of this kind with an acrylic acidester to be conducted in the presence of an alkaline catalyst, such assodium amide or potassium ethylate. However, in that case the estergroup has such an adverse influence on the reactivity of the double bondin the acrylic acid ester that for most ketones the addition takes placeat a very low efficiency. In the addition of methyl acrylate to methylbenzyl ketone, however, an efficiency of 82% is reached, which,probably, should be attributed to the activation of thealpha-hydrogen-atom, which is not only activated by the carbonyl groupbut also by the benzyl group.

DETAILED DESCRIPTION OF THE INVENTION

We have now found a process in which this addition can also beaccomplished at an attractive efficiency if the alpha-hydrogen-atom isactivated by the carbonyl group exclusively, and in which, in additionto esters of acrylic acid, other alpha-beta unsaturated carboxylic acidesters may also be added. The process according to the present inventionis characterized in that the reaction is carried out with the aid of aprimary amine, a Schiff base, or both, as catalysts, and that a reactionmixture is used containing an acid compound, As used herein, the termsprimary amine and Schiff base also comprise compounds in which, by theside of the primary amino group, respectively the N-substituted iminegroup, another functional group is present, for instance an amino acid.

In the addition reaction according to the present invention numerousketones may be applied as starting product, and generally containingfrom 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, and includeacetone, methyl ethyl ketone, methyl propyl ketone, diethyl ketone,methyl isopropyl ketone, cyclopentanone, cyclohexanone, 2-methylcyclohexanone and 4-methyl cyclohexanone.

Various alpha-beta unsaturated carboxylic acid esters may be used,derived from acids having from 3 to 8 carbon atoms, preferably 3 to 5carbon atoms in the process according to the present invention; howeverin practice the methyl and ethyl esters of acrylic acid, methacrylicacid and crotonic acid are of the most commercial importance.

As previously indicated, the present invention is characterized by theuse of a primary amine, Schiff base, or both, as a catalyst. We preferto use a primary amine containing from 1 to 6 carbon atoms in the alkylgroup which is either straight-chained or branched, preferably branched.Specific examples include methyl amine, ethyl amine, n-propyl amine,isopropyl amine, n-butyl amine, isobutyl amine, secondary butyl amine,secondary pentyl amine, n-hexyl amine, cyclopentyl amine, cyclohexylamine, hexamethylene diamine, ε-amino caproic acid and the Schiff basesof a ketone or aldehyde with one of the primary amines mentioned above.Extremely suitable catalysts are isopropyl amine, cyclohexyl amine andthe Schiff bases derived from these amines and the ketone to beconverted, and hence are the most preferred catalysts for use in theprocess disclosed. The catalyst quantity may be of course varied butwill generally be in the order of 0.01 to 0.25 mole of catalyst forevery mole of carboxylic acid ester.

Another characterizing feature of the present invention is that an acidor acid compound is employed which acid or acid compound is capable ofdecreasing the pH value of a neutral aqueous solution and/or whichcontains a functional acid group. In principle, nearly any acid may beused so long as it is non-reactive with the reactants and products.

Suitable acids and acid compounds include acetic acid, adipic acid,benzoic acid, phenol, caproic acid and the inorganic mineral acids suchas hydrochloric acid, phosphoric acid and sulphuric acid. Ammoniumchloride may also be used. Only a minor amount of an acid compound, forinstance 0.01-0.5 mole per mole of catalyst, is necessary for thereaction according to the present invention. If the catalyst should alsocontain an acid group, as in the case, for instance of ε-amino caproicacid, the use of an additional acid compound is not required.

Depending on the ratio between the ketone and the carboxylic acid ester,di-addition product can be formed concurrently with the mono-additionproduct, unless only one hydrogen atom is present in the alpha positionon the ketone. If the formation of di-addition product is possible, theformation of mono-addition product can be favored by using a ketone tocarboxylic acid ester ratio greater than 1:1, otherwiseketone:carboxylic acid ester ratios may generally vary from about 1:4 toabout 10:1.

The process according to the present invention is preferably conductedat a temperature between about 75 and 250° C., for at a temperature inexcess of 250° C. the efficiency is influenced adversely byside-reactions, while on the other hand at a temperature below 75° C.,the reaction proceeds too slowly for practical efficiency. The pressureis not critical and may be varied within rather wide limits. Incombination with the temperature, the pressure should, of course, beselected such that the reaction is conducted in the liquid phase,whether or not a solvent or a distributing agent is employed. However,if a solvent or a distributing agent (diluent) is used, any inertsolvent or distributing agent inert to the reactants, catalyst(s) andproducts will be suitable in principle. Illustrative materials includebenzene, toluene, cyclohexane, n-hexane and chlorobenzene. The use of asolvent or diluent is optional as it is not required for the process.

In the process according to the present invention the ketone, the ester,or both, can be wholly or partly converted depending in part on thereaction conditions. After the desired conversion has been reached, thereaction mixture may be separated into its various components bydistillation, in which, beside the desired product, a fraction can beobtained which is rich in catalyst and which can be reused andrecirculated.

Delta-keto-acid esters of the present invention are known compounds andare useful in a number of different applications. For example, they maybe used as starting products for the preparation of other valuableproducts. For instance, if in the process according to the presentinvention one starts from a cyclohexanone, optionally alkyl substituted,a delta-keto-acid ester is obtained which can be converted, according toU.S. Pat. No. 3,442,910, the disclosure of which is hereby incorporatedby reference, into the correspondingly substituted dihydrocoumarin,which is useful to the fragrances industry. Another use is in thepreparation of dihydroresorcinol, optionally substituted, from thedelta-keto-acid ester obtained from an alphatic ketone; see A. N. Kostand L. G. Ovseneva, Zhurnal Obschchei Khimii, volume 32, page 3983.Other uses will be apparent to the skilled chemist.

The process according to the invention will be in more detail in thefollowing examples in which all parts and described percentages are byweight unless otherwise indicated.

EXAMPLE 1 Preparation of 4-oxopentane-1-carboxylic acid methyl ester

Acetone (1740 g), methyl acrylate (645 g), isopropyl amine (25 g) andbenzoic acid (2.1 g) are charged into a 5 litter autoclave. The mixturein the autoclave is then heated to 160° C. at autogenic pressure andmaintained at this temperature for 2 hours. The reaction mixture is thencooled rapidly and transferred to a distillation flask. By distillationat atmospheric pressure the mixture is separated into 2011 g ofdistillate boiling below 125° C. and 380 g of residue. According togaschromatographic analysis the distillate contains 1580 g of acetoneand 377 g of methyl acrylate.

According to gaschromatographic analysis the residue contains 323 g ofthe methyl ester of 4-oxopentane-1-carboxylic acid.

By fractional distillation a main fraction of 312.7 g having a boilingpoint of 92°-93° C. at 10 mm Hg is obtained which, according togaschromatographic and spectrometric analysis, consists of pure4-oxopentane-1-carboxylic acid methyl ester (refractive index 20/n_(D)=1.4288).

41.5% of the total quantity of methyl acrylate has been converted andcalculated in relation to the amount of converted acetone, theefficiency amounts to 81%, and to 72% referred to the quantity ofconverted methyl acrylate.

EXAMPLE 2 Preparation of 4-oxopentane-1-carboxylic acid methyl ester

Acetone (348 g), methyl acrylate (172 g), isopropyl amine (4 g) andbenzoic acid (0.3 g) are charged into a 1 liter autoclave. The molarratio of acetone to methyl acrylate is 3:1. The mixture is then heatedfor 2 hours at 175° C. at autogenic pressure, then cooled rapidly andseparated by fractionating distillation at reduced pressure into thefollowing fractions:

(a) Fraction having a boiling point below 92° C. at 10 mm Hg weight392.2 g.

(b) Fraction having a boiling range of 90°-96° C. at 10 mm Hg weight73.9 g.

(c) Fraction having a boiling range of 96°-168° C. at 10 mm Hg weight1.8 g.

(d) Fraction having a boiling range of 168°-175° C. at 10 mm Hg weight21.8 g.

The fractions so obtained were then analyzed gaschromatographically andspectrometrically, indicating the following results:

Fraction (a) contains acetone, methyl acrylate, N-isopropyl acetonimineand (2-carbomethoxyethyl)-isopropyl amine. According to the quantitativeanalysis the fraction contains 25.8% by weight of methyl acrylate.Fraction (b) contains 95.1% by weight of 4-oxopentane-1-carboxylic acidmethyl ester. Fraction (d) consists of a mixture of diesters composed of70% by weight of dimethyl ester of 3-acetyl-pentane dicarboxylicacid-1.5 and 21% by weight of dimethyl ester of 4-oxoheptanedicarboxylic acid-1.7.

41% of the total quantity of methyl acrylate has been converted.Calculated with respect to converted methyl acrylate the efficiency in4-oxopentane-1-carboxylic acid methyl ester amounts to 59%, and indi-addition products to 21%.

EXAMPLE 3 Preparator of 4-oxopentane-1-carboxylic acid methyl ester

Acetone (1540 g), methyl acrylate (430 g) and benzoic acid (2 g) arecharged into a 5 liter autoclave and heated to 165° C. at autogenicpressure. Subsequently, over a period of about 5 minutes a solutionconsisting of isopropyl amine (24 g), benzoic acid (0.5 g) and acetone(200 g) is pumped into the autoclave, the resulting mixture being keptat 165° C. for 3 hours. The reaction mixture is cooled and transferredto a distillation flask.

By distillation at atmospheric pressure the reaction mixture isseparated into 1801 g of distillate, boiling below 125° C., and 379.3 gof residue.

According to gaschromatographic analysis the distillate contains 1581 gof acetone and 207 g of methyl acrylate, the residue containing 302 g ofmethyl ester of 4-oxopentane-1-carboxylic acid.

52% of the total amount of methyl acrylate has been converted.Calculated with respect to the quantity of converted acetone theefficiency amounts to 76%, and to 81% referred to the quantity of methylacrylate.

EXAMPLE 4 Preparation of 3-methyl-4-oxo-pentane-1-carboxylic acid ethylester

Methyl ethyl ketone (360 g), ethyl acrylate (125 g), isopropyl amine (4g) and benzoic acid (0.4 g) are charged into a 1 liter autoclave. Themixture is heated for 3 hours at 170° C. at autogenic pressure. Themolar ratio of methyl ethyl ketone to ethyl acrylate was 4:1.Subsequently, the reaction mixture is cooled, transferred to adistillation flask, and separated by distillation into:

(a) Fraction boiling below 98° C. at 9 mm Hg, the weight being 401.2 g.

(b) Fraction having a boiling range of 98°-102° C. at 9 mm Hg, theweight being 53.9 g.

(c) Residue having a weight of 28.9 g.

Fraction (a) contains 322 g of methyl ethyl ketone and 73.8 g of ethylacrylate.

Fraction (b) contains 95% by weight of ethyl ester of3-methyl-4-oxopentane-1-carboxylic acid and 2% by weight of ethyl esterof 4-oxo-hexane-1-carboxylic acid. 41% of the total amount of ethylacrylate has been converted. The efficiency in ethyl ester of3-methyl-4-oxo-pentane-1-carboxylic acid amounts to 56% referred to thequantity of converted methyl ethyl ketone, and to 58% referred to thequantity of converted ethyl acrylate.

EXAMPLE 5 Preparation of methyl 3-(2-oxocyclohexyl) propionate

Cyclohexanone (147.0 g), methyl acrylate (86.0 g), cyclohexyl amine (5.0g) and benzoic acid (0.5 g) are charged into a 1 liter flask fitted witha stirrer and a refux cooler. The mixture is heated to 100° C. withstirring. Subsequently, heating is continued such that the mixture keepsboiling gently. After 20 hours, the temperature in the flask has risento 155° C. The reaction mixture is then separated by distillation into afraction boiling below 140° C. at 13 mm Hg (weight 56.1 g), a secondfraction having a boiling range of 140° to 144° C. at 13 mm Hg (weight157.0 g) and a higher-boiling residue (weight 24.9 g).

According to gaschromatographic analysis the first distillate fractioncontains 52.3 of cyclohexanone and 1.2 g of methyl acrylate. The seconddistillate fraction contains 154.9 of methyl3-(2-oxocyclohexyl)-propionate product.

The efficiency in methyl-3-(2-oxocyclohexyl)-propionate amounts,therefore, to 85% calculated on the quantity of methyl acrylateconverted, and to 87% referred to the quantity of cyclohexanoneconverted.

EXAMPLE 6 Preparation of methyl-3-(1-methyl-2-oxocyclohexyl)propionateand methyl-3-(3-methyl-2-oxocyclohexyl)propionate

In the manner of Example 5, 2-methyl cyclohexanone (168 g) is reactedwith methyl acrylate (86 g) in the presence of cyclohexyl amine (5 g)and benzoic acid (0.5 g).

The reaction mixture so obtained is separated by distillation into afraction boiling below 73° C. at 0.1 mm Hg (weight 87.0 g), a secondfraction having a boiling range of 73°-76° C. at 0.1 mm Hg (weight 132.5g) and a higher-boiling residue (weight 36.1 g).

The first distillate fraction contains 72.8 g of 2-methyl cyclohexanoneand 4.3 g of methyl acrylate.

The second distillate fraction contains 89% by weight bymethyl-3-(1-methyl-2-oxocyclohexyl)-propionate and 9% by weight ofmethyl-3-(3-methyl-2-oxocyclohexyl)-propionate

The efficiency in methyl-3-(1-methyl-2-oxocyclohexyl)-propionate amountsto 63% calculated on the methyl acrylate converted, and 70% calculatedon the 2-methyl cyclohexanone converted.

The efficiency in methyl-3-(3-methyl-2-oxocyclohexyl)-propionate amountsto 6% calculated on the methyl acrylate converted, and 7% calculated onthe 2-methyl cyclohexanone converted.

EXAMPLE 7 Preparation of methyl-3-(2-oxocyclohexyl)-propionate

Cyclohexanone (4.9 g), methyl acrylate (4.3 g), 2-butyl amine (0.3 g)and benzoic acid (0.03 g) are reacted together in a stainless steel tubehaving a capacity of 15 ml. The tube is sealed and heated at atemperature of 160° C. for 3 hours.

The tube is then cooled rapidly and the reaction mixture (9.5 g)analyzed gaschromatographically.

The mixture contains 8.9% by weight of cyclohexanone, 21.1% by weight ofmethyl acrylate and 76.0% by weight ofmethyl-3-(2-oxocyclohexyl)-propionate. The methyl acrylate conversionamounts therefore to 95%. The efficiency inmethyl-3-(2-oxocyclohexyl)-propionate amounts to 95% calculated on thequantity of cyclohexanone converted, and to 83% calculated on thequantity of methyl acrylate converted.

EXAMPLES 8-14 Preparaton of 4-oxopentane-1-carboxylic acid methyl ester

In a number of stainless steel tubes having a capacity of 15 ml amixture of acetone (5.8 g, 0.1 mole) and methyl acrylate (2.15 g, 0.025mole) is heated at 170° C. for 2 hours, together with a primary amine (5mol.-% referred to methyl acrylate) and an acid (0.25 mol.-% referred tomethyl acrylate) both as identified in the following table.

Subsequently, the tubes are cooled rapidly, following which the contentsof the tubes is analyzed gaschromatographically, and the conversion ofthe methyl acrylate, as well as the efficiency in the methyl ester of4-oxopentane-1-carboxylic acid product, referred to the converted methylacrylate, is determined.

The results of these experiments are given in the following table:

    __________________________________________________________________________    Example                                                                       No.   8    9    10   11   12  13  14                                          __________________________________________________________________________    catalyst                                                                            iso- 2-butyl-                                                                           n-hexyl-                                                                           cyclo-                                                                             iso-                                                                              ani-                                                                              n-iso-                                            propyl                                                                             amine                                                                              amine                                                                              hexyl                                                                              propyl                                                                            line                                                                              propyl                                            amine          amine                                                                              amine   acetone                                                                       imine                                       acid  benzoic                                                                            benzoic                                                                            benzoic                                                                            benzoic                                                                            acetic                                                                            capro-                                                                            benzoic                                           acid acid acid acid acid                                                                              ic  acid                                                                      acid                                            conver-                                                                             61.6 57.5 64.3 61.2 34.6                                                                               5.8                                                                              44.2%                                       sion of                                                                       methyl                                                                        acryl-                                                                        late (%)                                                                      efficiency                                                                          68.0 57.7 48.1 71.1 48.7                                                                              77.4                                                                              55.8%                                       referred to                                                                   converted                                                                     methyl                                                                        acrylate                                                                      __________________________________________________________________________

EXAMPLE 15 Preparation of 2-methyl-4-oxo-pentane-1-carboxylic acid

Acetone (232 g), methyl crotonate (100 g), isopropyl amine (3 g) andbenzoic acid (0.3 g) are collected. The mixture is heated at 180° C. for3 hours at autogenic pressure. Subsequently, the reaction mixture iscooled, transferred to a distillation flask, and separated bydistillation into:

(a) Fraction boiling below 95° C. at 10 mm Hg, the weight being 300.2 g.

(b) Fraction having a boiling range of 95°-100° C. at 10 mm Hg, theweight being 21.5 g.

(c) Residue having a weight of 7.0 g.

Fraction (a) contains 216.0 of acetone and 79.9 of methyl crotonate.

Fraction (b) contains 19.8 g of methyl ester of2-methyl-4-oxo-pentane-1-carboxylic acid.

20% of the total amount of methyl crotonate was converted. Theefficiency in methyl ester of 2-methyl-4-oxo-pentane-1-carboxylic acidamounted to 45% calculated on the quantity of acetone converted, and to62% calculated on the quantity of methyl crotonate converted.

What is claimed is:
 1. Process for the preparation of a delta-keto-estercomprising reacting together in the liquid phase at a temperature ofabout 75° to 250° C. of an ester of an alpha-beta unsaturated carboxylicacid derived from acids having from 3 to 8 carbon atoms with a ketonehaving 3 to 10 carbon atoms, provided that said ketone has at least onehydrogen atom in the alpha position thereof, in the presence of primaryamine containing from 1 to 6 carbon atoms, a Schiff base of said amine,or both, and an acid compound to form the correspondingdelta-keto-ester.
 2. The process according to claim 1 wherein 0.01-0.25mole of catalyst is applied per mole of carboxylic acid ester.
 3. Theprocess according to claim 1 wherein said catalyst is isopropyl amine,cyclohexyl amine, or a Schiff base formed from said ketone and from oneof said primary amines.
 4. The process according to claim 1 wherein saidalpha-beta unsaturated carboxylic acid is acrylic acid, methacrylic acidor crotonic acid.
 5. The process according to claim 1 wherein saidketone is acetone, methyl ethyl ketone, methyl propyl ketone, diethylketone, methyl isopropyl ketone, cyclopentanone, cyclohexanone, 2-methylcyclohexanone or 4-methyl cyclohexanone.
 6. The process according toclaim 1 wherein the ratio of said ketone to said carboxylic acid esteris greater than 1:1.
 7. The process of claim 1, wherein said primaryamine, said Schiff base or said both and said acid compound are presentin a catalytic amount effective to form said delta-keto-ester. 8.Process for the preparation of a delta-keto-ester comprising reactingtogether in the liquid phase at a temperature of about 75° to 250° C.(1) an ester of an alpha-beta unsaturated carboxylic acid derived fromacids having from 3 to 8 carbon atoms with (2) an aliphatic ketonehaving from 3 to 10 carbon atoms, provided that said ketone has at leastone hydrogen atom in the alpha position thereof, in the presence of aprimary amine containing from 1 to 6 carbon atoms, a Schiff base of saidamine, or both, and an acid compound to form the correspondingdelta-keto-ester.
 9. Process for the preparation of a delta-keto-estercomprising reacting together in the liquid phase at a temperature ofabout 75° to 250° C. of an ester of an alpha-beta unsaturated carboxylicacid derived from acids having from 3 to 8 carbon atoms withcyclohexanone in the presence of a primary amine containing from 1 to 6atoms, a Schiff base of said amine, or both, and an acid compound toform the corresponding delta-keto-ester.